Functional interplay between melatonin receptor-mediated antiproliferative signaling and androgen receptor signaling in human prostate epithelial cells: Potential implications for therapeutic strategies against prostate cancer

Recently, a novel melatonin MT ₁ receptor-mediated antiproliferative signaling mechanism involving transcriptional up-regulation of p27 ^Kip1 due to paralleled stimulation of protein kinase A (PKA) and protein kinase C (PKC), as a result of respective dual activation of upstream Gα _s and Gα _q, has been reported in 22Rv1 and RWPE-1 human prostate epithelial cells. Here, we demonstrate that melatonin inhibits the proliferation of LNCaP and VCaP prostate cancer cells via activation of the same MT ₁ receptor-mediated antiproliferative signaling pathway. Knockdown of the expression of wild-type androgen receptor (AR) and/or structural/functional AR variants in LNCaP, VCaP, 22Rv1, and RWPE-1 cells resulted in abrogation of melatonin receptor-mediated antiproliferation, indicating that the antiproliferative signaling pathway MT ₁/ (Gα _s) PKA + (Gα _q) PKC/p27 ^Kip1 activated by melatonin in human prostate epithelial cells is AR dependent. Furthermore, melatonin was shown to decrease androgen/AR-mediated transactivation of the prostate-specific antigen promoter in the prostate epithelial cell lines. Together, our data indicate the presence of reciprocal functional interactions between MT ₁ receptor and AR signaling in malignant and nontumorigenic prostate epithelial cells. Notably, the dual actions of the MT ₁ receptor-mediated antiproliferative signaling, leading to down-regulation of activated AR signaling and up-regulation of p27 ^Kip1, constitute the mechanistic basis for the potential use of melatonin in chemoprevention of prostate cancer, as well as in a novel therapeutic strategy, comprising a combination of melatonin repletion and androgen depletion, for the treatment of advanced or relapsed disease.